AVN944 Shows Potent Antiproliferative Activity in Human Endothelial Cells
18 April 2007 - 9:30PM
PR Newswire (US)
GERMANTOWN, Md., April 18 /PRNewswire-FirstCall/ -- Avalon
Pharmaceuticals, Inc. (NASDAQ:AVRX), today described the potent
antiproliferative activity of AVN944 in human endothelial cells
(HUVEC), and showed that the compound prevents blood vessel
formation in a mouse model. The newly elucidated antiangiogenic
properties of the compound were examined in a study poster
entitled, "Antiangiogenic Properties of AVN944, A Potent Inhibitor
of IMPDH," presented at the American Association for Cancer
Research Annual Meeting held April 14-18, 2007, in Los Angeles.
"Results of this study provide new insight into the mechanism of
action of AVN944," stated Zoe Weaver, Ph.D., staff scientist at
Avalon and lead investigator in the study. "The suppression of
blood vessel growth, without any adverse effects to the mice, gives
us a strong rationale to include solid tumors, especially those
that may be more sensitive to agents that inhibit tumor
angiogenesis, in our Phase II trials." AVN944 is an orally
available inhibitor of inosine monophosphate dehydrogenase (IMPDH)
1 and 2. IMPDH2 is highly upregulated in many malignancies,
including hematologic cancers, and is required for the de novo
production of guanine nucleotides. AVN944 is a potent inhibitor of
cancer cell proliferation and elicits a specific set of cellular
responses directly related to depletion of cellular guanosine
triphosphate (GTP) pools. Recent studies of IMPDH inhibitors
suggest that they may elicit antiangiogenic effects and could
provide added benefit as a cancer therapy through blockade of tumor
angiogenesis. To investigate this approach, scientists at Avalon
evaluated AVN944 in a series of angiogenesis assays to determine
the potential utility of this drug as an antiangiogenic agent for
cancer treatment. As a result, AVN944 was found to potently inhibit
proliferation of HUVECs. This antiproliferative activity was
reversed by the addition of guanine, indicating that AVN944 is
inhibiting IMPDH activity and depleting GTP pools in endothelial
cells. Other in vitro assessments of AVN944 activity in endothelial
cells included a comprehensive analysis of global gene expression
changes resulting from IMPDH inhibition in these cells. The gene
expression signature induced by AVN944 in endothelial cells was
indicative of GTP metabolism and cell cycle inhibition, similar to
gene expression profiles exhibited by cancer cell lines.
Additionally, treatment of Matrigel plug- bearing mice with AVN944
inhibited the growth of new blood vessels to a similar or greater
degree than mycophenolate mofetil, an FDA-approved
immunosuppressant drug. Avalon investigators next plan to expand
the AVN944 preclinical program to include rodent solid tumor
models. Avalon's results, detailing the potent inhibition of
endothelial cells in vitro combined with inhibition of angiogenesis
in an in vivo model, could position this drug for rapid development
as a novel antiangiogenic agent for cancer therapy. About AVN944
AVN944 is an oral small molecule drug candidate that inhibits
inosine monosphospate dehydrogenase (IMPDH), an enzyme that is
critical for cells to be able to synthesize guanosine triphosphate
(GTP), a molecule required for DNA synthesis and cellular
signaling. IMPDH is over expressed in some cancer cells, especially
in the case of hematological malignancies. In laboratory
experiments, AVN944 has been shown to inhibit IMPDH activity in
cells, and suppress pools of GTP. Anticancer activities of IMPDH
inhibitors correlate with sustained depletion of GTP pools both in
cellular models and in human subjects. AVN944 appears to have a
selective effect on cancer cells in that deprivation of GTP in
normal cells results in a temporary slowing of cell growth, while
GTP deprivation in cancer cells induces cell death, or apoptosis.
Results from preclinical studies of AVN944 indicate that AVN944
inhibited the proliferation of lymphoid and myeloid cells, the
principal cells involved in the most common types of human
leukemias. In a single-dose, dose- escalation Phase I clinical
trial of AVN944 conducted in the United Kingdom in healthy
volunteers, AVN944: (1) was well tolerated at all tested doses with
no notable side effects; (2) demonstrated good pharmacokinetic
properties; and (3) had a significant inhibitory effect on IMPDH
enzyme activity. Avalon filed an IND with the FDA in August 2005
and initiated U.S. Phase I clinical trials in January 2006 for the
treatment of hematological cancers. About Avalon Pharmaceuticals
Avalon Pharmaceuticals is a biopharmaceutical company using its
proprietary technology, AvalonRx(R), to discover and develop cancer
therapeutics. Avalon has a lead product in Phase I clinical
development (AVN944 - IMPDH inhibitor), as well as preclinical
programs to discover inhibitors for the beta-catenin and aurora
pathways now in late stage lead candidate optimization. Avalon also
has discovery programs on modulators of survivin function and a
drug discovery program targeting the MYC oncoprotein, one of the
most important and previously intractable cancer targets. The
company has value generating partnerships with Merck, MedImmune,
Medarex, and Novartis. Avalon Pharmaceuticals was established in
1999 and is headquartered in Germantown, Md. Safe Harbor Statement
This announcement contains, in addition to historical information,
certain forward-looking statements that involve risks and
uncertainties, in particular, related to progress in our drug
discovery programs and our collaborations, and clinical progress in
the development of AVN944. Such statements reflect the current
views of Avalon management and are based on certain assumptions.
Actual results could differ materially from those currently
anticipated as a result of a number of factors, risks and
uncertainties including the risk that the discovery programs and
collaborations may not be successful and that AVN944 will not
progress successfully in its clinical trials, and other risks
described in our SEC filings. There can be no assurance that our
development efforts will succeed, that AVN944 will receive required
regulatory clearance or, even if such regulatory clearance is
received, that any subsequent products will ultimately achieve
commercial success. The information in this Release should be read
in conjunction with the Risk Factors set forth in our 2005 Annual
Report on Form 10-K and updates contained in subsequent filings we
make with the SEC. Contacts: Avalon Pharmaceuticals, Inc. Noonan
Russo David Muth Greg Geisman Executive Vice President Tel: (619)
814-3510 & Chief Business Officer Tel: (301) 556-9900 Fax:
(301) 556-9910 The Trout Group LLC Email: Chad Rubin (Investors)
Tel: (646) 378-2947 DATASOURCE: Avalon Pharmaceuticals, Inc.
CONTACT: David Muth, Executive Vice President & Chief Business
Officer of Avalon Pharmaceuticals, Inc., +1-301-556-9900, or fax
+1-301-556-9910, or , or Greg Geisman of Noonan Russo,
+1-619-814-3510, or Investors, Chad Rubin of The Trout Group LLC,
+1-646-378-2947 Web site: http://www.noonanrusso.com/
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